The present invention relates to new uses of certain orally deliverable pharmaceutical formulations containing the selective cyclooxygenase-2 inhibitory drug celecoxib, for fast relief of pain, and for manufacture of medicaments useful in treatment of pain.
Numerous compounds have been reported having therapeutically and/or prophylactically useful selective cyclooxygenase-2 inhibitory effect, and have been disclosed as having utility in treatment or prevention of specific cyclooxygenase-2 mediated disorders or of such disorders in general. Among such compounds are a large number of substituted pyrazolyl benzenesulfonamides as reported in U.S. Pat. No. 5,760,068 to Talley et al., including for example the compound 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-y1]benzenesulfonamide, also referred to herein as celecoxib. Celecoxib has the structure shown in formula (I): 
A need for orally deliverable pharmaceutical compositions giving fast relief of pain exists. A particular need exists for such compositions giving fast relief of pain through selective inhibition of cyclooxygenase-2 (COX-2), without the undesirable side effects associated with inhibition of cyclooxygenase-1 (COX-1) that can occur with conventional non-steroidal anti-inflammatory drugs (NSAIDs). An especial need exists for such compositions giving fast relief of pain through selective inhibition of COX-2, yet exhibiting an onset of effective pain relief at least as rapid as standard NSAIDs used in the art, for example ibuprofen.
Celecoxib is well known as a highly effective selective COX-2 inhibitory drug and is widely prescribed for treatment of chronic inflammatory diseases such as rheumatoid arthritis and osteoarthritis. Celecoxib is available under the trademark Celebrex(copyright) of Pharmacia Corporation in capsule dosage forms containing 100 mg or 200 mg of the drug. Although these dosage forms can provide very effective relief of pain, they can, at least in some acute pain situations, exhibit a slower onset of pain relief than a standard NSAID such as ibuprofen.
A suspension of particulate celecoxib in a vehicle of apple juice is disclosed in Ecuador Patent Application No. 98-2761 (xe2x80x9cEC 98-2761xe2x80x9d which corresponds to WO 00/32189, Jun. 8, 2000). See in particular Example 13 therein, which describes preparation of such a suspension by dissolving celecoxib in ethanol containing 5% polysorbate 80 and adding the resulting mixture to apple juice prior to oral administration to 10 healthy male subjects. The dose administered was 300 mg celecoxib. An equal 300 mg dose was administered for comparison, in the form of three 100 mg capsules containing formulated celecoxib having a D90 particle size of about 37 xcexcm (i.e., 90% by weight of celecoxib particles in the formulation were smaller, in their longest dimension, than about 37 xcexcm). Pharmacokinetic parameters disclosed indicate that the suspension gave a higher Cmax, shorter Tmax and shorter Txc2xd than the capsules as indicated in Table 1 below, where Cmax is the average maximum blood plasma concentration of celecoxib following administration, Tmax is the average length of time from administration until Cmax is reached, and Txc2xd is the average terminal half-life of blood plasma concentration of celecoxib following Tmax.
Ibuprofen in a typical acute pain relief dose of 400 mg normally provides an adequate level of suppression of pain, for example post-surgical pain, by about 1 hour after administration. Celecoxib in capsule form normally takes longer, for example about 2 hours, to achieve a similar level of pain suppression. No suggestion is made in above-cited EC 98-2761 that the apparently modest reduction in Tmax exhibited by the disclosed suspension by comparison with the capsule formulation, when administered in a 300 mg dose, could be associated with a major improvement in onset of pain relief, or that the suspension formulation of celecoxib could be at least comparable with ibuprofen in onset of pain relief.
Above-cited EC 98-2761 merely discloses in general terms that compositions of the invention disclosed therein, i.e., including the disclosed capsule formulations as well as the suspension composition of Example 13 thereof, are effective xe2x80x9cfor pain management generally (particularly post-oral surgery pain, post-general surgery pain, post-orthopedic surgery pain, and acute flares of osteoarthritis)xe2x80x9d. Nevertheless, this reference contains no suggestion that the suspension composition might provide an effective pain relieving amount of celecoxib nor was it appreciated by this reference that an effective pain-relieving concentration of 250 nm/ml plasma or greater could be achieved in a rapidly bioavailable formulation. This is particularly in view of the extensive binding of celecoxib to plasma albumin which was known to occur following oral administration (Davies et al., Clin. Pharmacokinet. 38:225-242, 2000). Thus, one could not have predicted that a particular plasma concentration would produce analgesia.
Australian Patent Applications No. 200042711, No. 200043730 and No. 200043736 disclose compositions comprising a selective COX-2 inhibitory drug, a 5HT1 receptor agonist and caffeine, said to be useful for treating migraine.
Although objectives of the present invention are not limited to any particular measure of analgesic response, a method of providing analgesia with an onset time of 60 minutes or less, especially 30 minutes or less and ideally 15 minutes or less, by oral administration of a celecoxib composition would be an important advance in the art.
It has now surprisingly been discovered that celecoxib can provide acceptable relief of acute pain within about 60 minutes or less after oral administration, in some cases much less than 60 minutes, for example as little as about 15 to about 45 minutes, after oral administration, if it is formulated and administered in such a way as to give a particular pharmacokinetic profile as defined below.
Accordingly, there is now provided a therapeutic method comprising orally administering to a mammalian, preferably human, subject in need of analgesia an effective pain-relieving amount of a composition comprising celecoxib (herein also referred to as a celecoxib composition) formulated in such a way as to provide, when tested in fasting humans in accordance with standard pharmacokinetic practice, a blood plasma concentration profile of celecoxib in which a concentration of about 250 ng/ml is attained not later than about 30 minutes after oral administration. The plasma concentrations of 250 ng/ml or greater achieved by the compositions and methods of the present invention at or before 30 minutes after oral administration and, more preferably, at or before 15 minutes after oral administration, are effective pain-relieving plasma concentrations.
It has not previously been known that fast absorption of celecoxib, as indicated by such a blood plasma concentration profile, is important in achieving fast onset of analgesic response. As noted above, celecoxib is known to be extensively bound to plasma albumin following oral administration (Davies et al., supra) such that one could not have predicted that a particular plasma concentration would produce analgesia.
There is also provided a method of use of celecoxib, formulated in such a way as to provide, when tested in an effective pain-relieving amount in fasting humans in accordance with standard pharmacokinetic practice, a blood plasma concentration profile of celecoxib in which a concentration of about 250 ng/ml is attained not later than about 30 minutes after oral administration, in preparation of a medicament for rapid relief of pain in a mammalian, preferably human, subject.
The phrase xe2x80x9cin need of analgesiaxe2x80x9d as applied to a subject herein embraces a subject suffering mild to intense pain at the time of administration of the celecoxib composition, as well as a subject that can reasonably be expected to have an imminent onset of mild to intense pain, e.g., within about 1 to about 2 hours and especially within about 30 minutes, if no analgesic is administered. An illustrative example of a situation where a subject can reasonably be expected to have such an imminent onset of pain is a period immediately following surgery under local anesthetic, as effects of the local anesthetic wear off.
What constitutes an effective pain-relieving amount, or dose, of a celecoxib composition according to the invention depends, among other factors, on the body weight of the subject and the intensity of the pain being treated. Normally an effective celecoxib dose will be found in the range of about 1 to about 6 mg/kg body weight. For an average 75 kg subject, this range equates to a celecoxib dose of about 75 to about 450 mg. Proportionately smaller or larger doses can be appropriate for subjects having lesser or greater body weight. Such a dose can be administered as needed, but typically administration 1 to about 4 times per day, in most cases 1 or 2 times a day, provides adequate continuing relief of pain.
An xe2x80x9ceffective pain-relieving concentrationxe2x80x9d or xe2x80x9ceffective pain-relieving plasma concentrationxe2x80x9d as used herein is intended to mean a plasma level in a patient which when tested in a standardized test involving patient scoring of the severity of pain, achieves a mean score indicating pain relief. In one such test as described hereinbelow, patients score pain on a scale of from 0 (no reduction in severity of pain) to 4 (complete relief of pain) and a mean score equal to or greater than a given value is deemed to constitute effective pain-relief. A mean score of 0.5 or greater and, more preferably, 1.0 or greater in such a test, as exemplified herein, is deemed to constitute effective pain relief. The skilled artisan will appreciate, however, that other approaches can be used to assess the severity of pain and relief from such pain.
Thus, one aspect of the present invention involves a therapeutic method for analgesia in which a composition comprising celecoxib is administered orally to a subject, in a formulation which provides detectable pain relief not later than about 30 minutes after oral administration. By xe2x80x9cdetectable pain reliefxe2x80x9d, it is meant that the formulation produces effective pain relief which is measurable by a standard method such as described above. For example, a formulation, which achieves a mean score of 0.5 or greater and, more preferably, 1.0 or greater on a scale of from 0 to 4 in a testing system as described above, is deemed to provide detectable pain relief. The invention is not limited to use of any particular type of formulation, so long as it exhibits the pharmacokinetic profile defined herein. Examples of suitable formulation types are described below.
Protocols for conducting human pharmacokinetic studies are well known in the art and any standard protocol can be used to determine whether a particular celecoxib formulation satisfies the pharmacokinetic criteria set out herein. An example of a suitable protocol is described below.
An advantage of the present invention is that relief of pain, even intense pain as can occur, for example, following oral, general or orthopedic surgery, is achieved significantly faster, i.e., in a significantly shorter time after administration, than is achievable with standard formulations of celecoxib.
A further advantage is that, by contrast with pain relief methods involving NSAIDs lacking selectivity for inhibition of COX-2, rapid relief of pain can be obtained without the side-effects commonly associated with COX-1 inhibition. Thus the method of the present invention is especially suitable where NSAIDs are contraindicated, for example in patients with peptic ulcers, gastritis, regional enteritis, ulcerative colitis or diverticulitis, patients with a recurrent history of gastrointestinal lesions, patients with gastrointestinal bleeding, coagulation disorders including anemia such as hypothrombinemia, hemophilia and other bleeding problems, or kidney disease, patients prior to surgery, or patients taking anticoagulants.
Other features and advantages of the invention will be in part apparent and in part pointed out hereinafter.